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A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-function

Menezes, DL and Holt, J and Tang, Y and Feng, J and Barsanti, P and Pan, Y and Ghoddusi, M and Zhang, W and Thomas, G and Holash, J and Lees, E and Taricani, L (2014) A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-function. Molecular Cancer Research .

Abstract

Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response (DDR) pathway factors, such as ataxia telangiectasia-mutated (ATM)/ATM- and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content g-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break repair (DSB) and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of g-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared to ATM wild-type cancer cells. In summary, single agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost. Implications: These data suggest that single agent ATR inhibitors have therapeutic utility and that ATR utilizes a complex and coordinated set of proteins to maintain genomic stability which could be further exploited

Item Type: Article
Additional Information: NIBR author: Menezes, DL institute: NIBR contributor address: Novartis Institutes for Biomedical Research at Emeryville, CA dmenezes1@gmail.comNovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CANovartis Institutes for Biomedical Research at Emeryville, CA
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/24237

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